PARENT SESSION

2L - Immunotoxicity - genotoxicity - ED
Poster Hall
8:30 AM - Wednesday, 30 April 2003
Chair: Hansen, P.D.¹, ¹

(WEP/104) Endocrine Activity of UV Filters and Effects on Development of Reproductive Organs, Brain and Gene Expression.

Schlumpf, Margret¹, Durrer, Stefan¹, Maerkel, Kirsten¹, Conscience, Marianne¹, Ma, Risheng¹, Lichtensteiger, Walter¹, ¹ Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland, Switzerland

ABSTRACT- We previously reported estrogenic activity of UV filters in vitro on MCF-7 cells, and uterotrophic activity in immature rats for 4-methylbenzylidene camphor (4-MBC), octylmethoxy-cinnamate, and benzophenone-3 (Bp-3) (Schlumpf et al., 2001). 3-benzylidene camphor (3-BC) has now also been shown to be uterotrophic. The in vitro and in vivo activity of 4-MBC has recently been confirmed by Tinwell et al. (2002), 3-BC is also estrogenic in fish (Holbech et al., 2002). We further observed that Bp-3 and homosalate act as androgen antagonists in MDA-MB-453-KB2 cells that express the human androgen receptor and are stably transfected with a luciferase reporter plasmid. - Administration of 4-MBC in chow to Long Evans rats from 10 weeks before mating until adulthood of F1 offspring (1.0, 0.66, 0.33, 0.1 g/ kg chow: 70, 47, 24, 7 mg/kg/day) resulted in a dose-dependent delay of male puberty from the lowest dose tested, without effect on female puberty onset, and in significant weight changes of testis, epididymis, seminal vesicles, ventral and dorsal prostate in adult offspring. Estrogen target gene mRNA levels were determined by Real Time PCR, with cyclophilin as reference gene, in reproductive organs and sexually dimorphic brain regions of adult offspring. Significant changes were observed in uterus of adult offspring (IGF-I, progesterone receptor (PR), androgen receptor (AR)) and different lobes of prostate (IGF-I, AR). Ventromedial hypothalamus (VMN) and medial preoptic region which are involved in control of sexual behavior and gonadal regulation, showed sex- and region-specific changes in mRNAs encoding for PR and ER alpha from 7mg/kg/day 4-MBC, with loss of sexually dimorphic PR mRNA expression in VMN. Acute estrogen challenge experiments in adult gonadectomized offspring, designed to assess estrogen sensitivity, are in progress. Our data indicate that 4-MBC can influence sexual development at peripheral and central levels of neuroendocrine organization, and induce longterm alterations in the expression of estrogen-regulated genes. (Supported by Swiss National Science Foundation (NRP50) and Swiss Environmental Protection Agency (BUWAL)).

Key words: development, UV filters, gene expression, antiandrogenic activity